Multiple sclerosis (MS) is a chronic and disabling disease. Worldwide, there are over 2.5 million people suffering from it, with more than 400,000 in the US alone. Although there is no known cure for MS, there are therapies that can effectively slow down the disease. These therapeutic regimens mainly aim to control symptoms and prevent further damages. For this strategy to be effective, we need to diagnose the disease early and characterize it accurately. However, at its early stage, MS is difficult to diagnose as is symptoms can mimic those of many other nervous system disorders. In the past decade, the use of brain and spinal MRI has greatly improved the diagnostic accuracy. However, it has also become increasingly clear that current clinical MRI protocols show only part of MS pathology, failing to reveal important changes occurring at the microscopic level. Furthermore, it is now recognized that standard MRI protocols do not reflect the severity of clinical symptoms. For example, we often see no change in MR findings even though clinical worsening has occurred. At the same time, clinical trials and emerging treatments are focusing increasingly on prevention of CNS injury and promotion of recovery from damages already occurred. Therefore, there is an urgent need for improved diagnostic and prognostic imaging tools that can evaluate the disease status more accurately. The hallmark of MS is loss of myelin which protects the axons and facilitates the transmission of nerve signals. Recent studies suggested that myelin has a unique magnetic susceptibility that can be measured by MRI. This unique magnetic property reduces the rate of MRI signal decay (R2*) and causes a positive frequency shift when demyelination occurs. If this magnetic property can be quantified accurately, it can be used as a powerful marker to initiate early treatment and to monitor treatment outcome. We are developing novel, accurate and clinical feasible techniques to image and quantify tissue magnetic susceptibility with high spatial resolution. In the proposed project, we will further develop and optimize this novel technique; we will determine the relationship between susceptibility and MS pathology; we will characterize susceptibility properties of MS brains in lesions and normal appearing white matter and gray matter; we will determine if susceptibility can be used as a marker for predicting disease progression and clinical disability. The expected outcome will facilitate the translation o this novel technique to the clinical management of MS. In addition to MS, the technique has a broad applicability in the imaging of many other neurological diseases and disorders.